Group A streptococcal cell walls (SCW) induce a biphasic pattern of hepatic granuloma formation and chronic, erosive polyarthritis in the LEW/N, but not the genetically similar F344/N rat. The first phase is an acute exudative response characterized by neutrophil accumulation and swelling which peaks at 3 days, recedes and is following by a chronic destructive mononuclear cell-mediated phase. In studies to identify the cellular and molecular mechanism of differential genetic susceptibility, macrophages from the two strains were compared for their responsiveness to SCW. Peritoneal macrophages exposed to SCW in vivo or in vitro were evaluated for inflammatory mediator and monokine production. The LEW/N macrophages were found to produce elevated levels of differentiation and proliferative factors compared to the F344/N which may promote chronic inflammation and provide a basis for the differential development of erosive polyarthritis in the SCW-treated LEW/N and F344/N animals. In order to further define the cellular and molecular mechanisms responsible for the acute and chronic phases of the SCW-induced inflammatory response, we have evaluated the effect of site-specific inhibitors on these processes. The anti- inflammatory corticosteroid, methylprednisolone (MP) ablates the acute response and consequently the chronic infiltration of mononuclear cells (articular index (AI) 9.1 vs 0.2). By comparison, flurbiprofen, a nonsteroidal anti-inflammatory drug, partially suppressed both the acute and chronic arthritis (AI 9.1 vs 2.1). Thus, each of these agents appears to act at different loci to modulate SCW-induced arthritis. By choosing drug combinations with different target specificities, it may be possible to interrupt several sites in this interdependent inflammatory process.